For the past two decades, we have been interested hi mechanisms that lead to cell injury or adaptation and survival in low O2 environment. At the time of this revised renewal's write-up, which coincides to about 4 1/2 years from the start of this cycle, we have learned considerably about the role of NHE. For example, we have made progress in defining the role of NHE in the response of neurons to hypoxia and investigating the effect of chronic hypoxia on the expression of transporters and enzyme activities. Of particular importance are our findings that the CA1 neuronal excitability is increased and that Na+ channel current density is augmented in the NHE1-/-. Although NHEs have a well defined function, evidence has been accumulating that NHEs may not be exchangers for Na+ and H+ only but may have other functions. For example, NHE1 has been recently found to interact with cytoskeletal proteins and play a role in cell differentiation and proliferation. Based on our results and the literature, our general hypothesis is that NHE (e.g. NHE 1) plays a major role under stressful conditions, such as in hypoxia and/or high CO2; the mechanisms underlying this role may not be related only to an exchange between Na+ and H+, but also to the role that NHEs play as signaling molecules. Our Specific Hypotheses and Aims are as follows: I) Hypoxia alters NHE function via specific signaling pathways (Ca++-mediated and Kinases) or via NHE expression; the attenuated response of the immature cell (as compared to the mature) to hypoxia is due, at least in part, to lower expression of NHEs or signaling molecules (e.g. PKC). II) The response of neurons and astrocytes to hypoxia is not only dependent on NHE 1 but also on specific NHE 1-interacting proteins and III) The response of neurons and astrocytes to hypercapnia depends on the presence of NHE; this response is different from that to hypoxia or to a combination of hypoxia/hypercapnia and depends on maturation in early life. We believe that this Project is interdependent with other Projects in the Program and is dependent on the Cores for various techniques and for chronically exposed mice to hypoxia/hypercapnia.